Thyroid cancer is the most common malignancy of endocrine glands, and over 37,000 new cases are predicted for 2008. Although most patients diagnosed with thyroid cancer will not die from this disease, a significant proportion of patients will develop recurrent or metastatic disease, and mutations in the gene encoding the serine/threonine l<inase BRaf are associated with these features. In addition, BRaf mutations are also detected in poorly- and un-differentiated thyroid cancers that portend a very poor prognosis. Mouse models of cancer have been constructed for many human cancer types, and can serve as important experimental and pre-clinical platforms. The genetic underpinnings of human thyroid cancer have begun to be elucidated, and mouse models of thyroid cancer have been developed using oncogenes identified in human tumors. However, these models rely upon transgenic expression of the oncogene using a heterologous thyroid-specific promoter, and do not recapitulate many features of human thyroid cancer. In the work supported by this proposal we will generate a series of carefully-constructed BRaf-dependent mouse models of thyroid cancer that will utilize endogenous conditional oncogene and tumor suppressor alleles that can be focally-induced in adult mice. As part of this proposal we will also generate a thyroid-specific CreER mouse that will be useful to the thyroid research community. We believe that these studies will forward our understanding of the cellular and molecular basis of thyroid cancer progression in mouse and man, further knowledge of the downstream effectors of BRaf during tumorigenesis, identify novel therapeutic targets, and develop important pre-clinical models for testing of novel therapeutic agents.